Copper and L-(?)-quebrachitol catalyzed hydroxylation and amination of aryl halides under air

Article abstract of DOI:10.1016/j.tetlet.2020.152222

L-(?)-Quebrachitol, a natural product obtained from waste water of the rubber industry, was utilized as an efficient ligand for the copper-catalyzed hydroxylation and amination of aryl halides to selectively give phenols and aryl amines in water or 95percent ethanol. In addition, the hydroxylation of 2-chloro-4-hydroxybenzoic acid was validated on a 100-g scale under air.

Full text of DOI:10.1016/j.tetlet.2020.152222

Journal Pre-proofs
Copper and L-(-)-Quebrachitol catalyzed hydroxylation and amination of aryl
halides under air
Xinjie Liang, Hui Li, Fangyu Du, Yongsheng Zhang, Jinhua Dong, Xuefei
Bao, Ying Wu, Guoliang Chen
PII:
S0040-4039(20)30689-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152222
TETL 152222
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Tetrahedron Letters
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Revised Date:
Accepted Date:
3 March 2020
29 June 2020
3 July 2020
Please cite this article as: Liang, X., Li, H., Du, F., Zhang, Y., Dong, J., Bao, X., Wu, Y., Chen, G., Copper and
L-(-)-Quebrachitol catalyzed hydroxylation and amination of aryl halides under air, Tetrahedron Letters (2020),
doi: https://doi.org/10.1016/j.tetlet.2020.152222
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Copper and L-(-)-Quebrachitol catalyzed
hydroxylation and amination of aryl halides
under air
Xinjie Liang, Hui Li, Fangyu Du, Yongsheng Zhang, Jinhua Dong, Xuefei Bao, Ying Wu, Guoliang Chen

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Copper and L-(-)-Quebrachitol catalyzed hydroxylation and amination of aryl halides
under air
Xinjie Lianga, Hui Lia, Fangyu Dua, Yongsheng Zhanga, Jinhua Donga, Xuefei Baoa,*, Ying Wub,*,
Guoliang Chena, *
a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
b Yunnan Institute of Tropical Crops, Jinghong 666100, China
* Corresponding author: spucgl@163.com (GL Chen); bxf551@163.com (XF Bao); ynbnwy@163.com (Y Wu).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
L-(-)-Quebrachitol，a natural product obtained from waste water of the rubber industry, was
utilized as an efficient ligand for the copper-catalyzed hydroxylation and amination of aryl halides
to selectively give phenols and aryl amines in water or 95% ethanol. In addition, the hydroxylation
of 2-chloro-4-hydroxybenzoic acid was validated on a 100-gram scale under air.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
L-(-)-Quebrachitol
Phenols
Aryl amines
Amination
Hydroxylation
1. Introduction
Phenols, aryl amines and their derivatives are important
intermediates in the pharmaceutical, chemical, and materials
industries.1,2 The development of mild and efficient methods for
their synthesis from readily available starting materials has gained
considerable attention. Among the reported methods, the
hydroxylation of aryl halides has been recognized as one of the
most valuable approaches.3 Efficient systems based on
palladium/phosphine catalysis were developed by Buchwald and
other groups.4 However, the use of precious metal catalysts and
toxic ligands has reduced their attractiveness. Recently, several
efficient copper-catalyzed procedures for the direct hydroxylation
of aryl halides were reported (Fig. 1). The groups of Taillefer and
You were the first to report that aryl halides could be hydrolyzed
by hydroxide salts in the presence of CuI and a ligand under mild
conditions.5 The groups of Zhou and Jiang also obtained phenols
from the corresponding aryl halides via hydroxylation catalyzed
by CuI and a ligand in water, and phase transfer catalysts (PTC),
such as n-Bu4NF or n-Bu4NBr, were essential for these
procedures.6 Feng and co-workers reported that CuI-nanoparticles
could catalyze the synthesis of phenols and aryl amines from aryl
halides under a nitrogen atmosphere without a ligand or an organic
solvent.7 Unfortunately, many of the reported reaction conditions
require a substantial amount of a mixed solvent or a PTC which
are difficult to recycle.
Figure 1. Selected methods for the synthesis of phenols and aryl
amines.
Considering the solubility of carboxylates, which dissolve well
in basic aqueous solutions, we speculated that if a suitable water-
soluble ligand could be found, the organic solvent and PTC would
not be essential. To develop an eco-friendly and practical protocol,
we report a method for the conversion of aryl iodides to phenols
via the combination of Cu2O and L-Quebrachitol in water (Fig. 2).
Unfortunately, this catalytic system was not applicable to water-
insoluble compounds. To our surprise, when we replaced water
with 95% ethanol (low toxicity, recyclable), the catalytic system

2
5 c
6 c
7 c
8
Glucose
Inositol
Cu2O
Cu2O
Cu2O
Cu2O
CuCl2
CuSO4
CuCl
CuI
Cu(OAc)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
NaOH 77
NaOH 79
NaOH 94
NaOH 93
NaOH 50
NaOH 20
NaOH 93
NaOH 60
also worked well, and few or no phenethyl ethers were produced.
Additionally, aryl amines could also be obtained from aryl halides
via the reaction in aqueous ammonia catalyzed by Cu2O and L-
Quebrachitol without a PTC or a mixed solvent.
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
L-Que
9
10
11
12
13
14
15
16
17d
18e
19f
20g
NaOH
KOH
CsCO3
K2CO3
0
92
0
0
NaOH 79
NaOH 94
NaOH 46
NaOH 39
a Reagents and conditions: 4-iodobenzoic acid (0.5 mmol), base (2 mmol), Cu-
catalyst (0.05 mmol), ligand (0.05 mmol), water (5 mL), air, 6 h. b % area by
HPLC. c argon atmosphere. d 3 equiv. of NaOH was used. e 6 equiv. of NaOH
was used. f 5 mol% of Cu2O was used. g 5 mol% of L-Que was used.
Figure 2. Practical synthesis of phenols and anilines from aryl halides.
L-Quebrachitol (1-L-(-)-2-O-methyl-chiro-inositol, L-Que) is
an optically active cyclitol which has been known in the literature
for over a century.8 The waste water of the rubber industry
represents the main source of L-Que and extraction technologies
have been developed to obtain L-Que on large scale.9 Herein, we
have utilized it as an efficient ligand for the copper-catalyzed
hydroxylation and amination of aryl halides.
Next, several aryl iodides with carboxyl groups were employed
to investigate the efficiency and scope of the L-Que/Cu2O
catalyzed system (Table 2). The hydroxylation proceeded under an
air atmosphere to afford the corresponding phenols in moderate to
excellent yields. A number of functional groups, for example
bromine, benzylic C-H bonds, nitro and alkenyl, were well
tolerated. Aryl iodides substituted only by carboxyl groups
afforded the desired products in excellent yields, and the position
of the carboxyl substitution had no obvious influence on the
hydroxylation (Table 2, entries 1-3). When chloro-substituted aryl
iodides were used, the hydroxylation only took place at iodine
leaving chlorine untouched (Table 2, entries 6-8). As for bromo-
substituted aryl iodides, acceptable yields could also be achieved
(Table 2, entries 9-11). In addition to the benzoic acids mentioned
above, good yields were obtained for substrates in which the
carboxyl groups were not directly linked to the benzene ring
(Table 2, entries 12-19). The performance of substrates with
2. Results and Discussion
Initially, we selected 4-iodobenzoic acid as a model substrate
to investigate the effect of Cu-catalysts, bases and ligands (Table
1). Selected water-soluble ligands reported in the literature,5, 10
such as glycolic acid, L-proline and triethanolamine, were
employed (10 mol%) at 100 oC in the presence of Cu2O (10 mol%)
under an argon atmosphere (Table 1, entries 2-4); however
acceptable results were not achieved. Encouraged by Sekar and co-
workers’ report that D-glucose could be used for the copper-
catalyzed synthesis of phenols from aryl halides,11 we investigated
the effect of D-glucose, inositol and L-Que. Gratifyingly, the
reaction proceeded well and gave the desired p-hydroxybenzoic
acid in good conversion when L-Que was employed (Table 1, entry
7). Meanwhile, no decrease of the conversion was detected when
the reaction was performed under air, implying that the inert
atmosphere was not necessary in this catalytic system (Table 1,
entry 8). After screening a variety of Cu-catalysts, CuCl and Cu2O
turned out to be the most efficient for this transformation (Table 1,
entries 9-13). Considering the stability under air and the cost, Cu2O
was selected for further optimization. Further inspection revealed
that KOH and NaOH gave similar results, while K2CO3 and CsCO3
were not suitable for this reaction (Table 1, entries 14-16).
Moreover, the amount of NaOH was also evaluated and the results
indicated that the conversion decreased when 3 equiv. of NaOH
was used (Table 1, entries 17). Further optimization to reduce the
catalyst loading showed that only 10 mol% of Cu2O and 10 mol%
of L-Que were required for quantitative conversion (Entries 19 and
20). Thus, the optimal conditions were Cu2O (10 mol%), L-Que
(10 mol%), NaOH (4 equiv.), in water under air.
o
electron-donating methoxy substituents were poor at 100 C, but
good at 120 oC or higher temperatures. To investigate the effect of
the carboxyl group, 1-(4-iodophenyl) ethenone and 1-iodo-4-
methoxybenzene were employed; the former was converted to the
corresponding phenol in high yield, but the latter was unreactive
(Table 2, entries 20-21). Understandably, the solubility of the
starting materials in water resulted in different reactivity.
Table 2. Direct hydroxylation of water-soluble aryl iodides.a
Entry
1
Product
Temp. (oC)
100
Yield (%)b
93
2
3
100
100
90
88
Table 1. Optimization of the Cu-catalyzed hydroxylation of 4-
iodobenzoic acid.a
4
100
79
Yield (%) b
5
6
100
100
74
83
Entry Ligand
Catalyst
Cu2O
Cu2O
Cu2O
Cu2O
Base
1 c
2 c
3 c
4 c
-
NaOH 15
NaOH 20
NaOH 16
NaOH 27
Glycolic acid
L
-
proline
Triethanolamine

3
activating group, such as 3-nitrobromobenzene, the corresponding
phenol was not afforded.
7
8
100
90
87
55
Inspired by these metal-catalyzed N-arylations, we wondered
whether N-arylation would take place when L-Que/Cu2O was
combined with aqueous ammonia. To our delight, aryl bromides
could be selectively converted to aryl amines in good to excellent
yields rather than diphenylamine (not detected) without a PTC or
a mixed solvent (Table 4). Aryl chlorides performed poorly in this
system (Table 4, entry 14).
9
100
100
71
77
Table 3. Direct hydroxylation of water-insoluble aryl iodides.a
10
Yield (%) b
96
11
100
86
Entry
1
Product
12
13
14
100
100
130
71
84
68
2
3
90
76
4
5
88
90
15
16
17
100
100
100
79
88
90
6
7
93
0
18
19
20
21
120
120
120
130
81
60
87
0
a Reagents and conditions: aryl iodide (0.5 mmol), Cu2O (0.05 mmol), L-Que
(0.05 mmol), NaOH (1.25 mmol), 95% ethanol (5 mL), 100 oC, air. b Isolated
yield (flash column chromatography on silica gel).
Table 4. Direct amination of aryl bromides.a
Entry
1
Product
Yield (%) b
97
a Reagents and conditions: aryl iodide (0.5 mmol), Cu2O (0.05 mmol), L-Que
(0.05 mmol), NaOH (2.0 mmol), water (5 mL), air. b Isolated yield (flash
column chromatography on silica gel).
2-Chloro-4-hydroxybenzoic acid,12
a
valuable synthetic
2
3
4
5
86
95
90
93
building block for the chemical and pharmaceutical industries, was
employed to validate the large-scale applicability of this method
(Fig. 3).
Figure 3. Results of the scale-up batch.
In order to solve the problem of poor reactivity using water-
insoluble compounds, we examined easily recycled and low toxic
organic solvents. We found that when 95% ethanol was used as a
solvent, iodobenzene could be selectively converted to phenols
instead of phenethyl ether (<4%). Next, the scope of aryl iodides
was investigated for this modified catalyst system (Table 3). In
general, aryl iodides gave the corresponding phenols in good to
excellent yields (Table 3, entries 1-6). However, aryl bromides
could not be hydrolyzed, and even in the case of a strongly
6
7
85
92

4
This work was financially supported by the China Postdoctoral
Science Foundation (No. 2019M661132), the Doctoral Scientific
Research Foundation of Liaoning Province (No. 2019-BS-227)
and the Program of Yunnan Science and Technology Department
(No. 2017jkys03).
8
93
90
89
9
10
References
1. Rappoport, Z. The Chemistry of Phenols, Wiley-VCH, Weinheim,
2003; Tyman, J. H. P. Synthetic and Natural Phenols, Elsevier,
New York, 1996.
2. Lawrence, S. A. Amines: Synthesis Properties and Application,
Cambridge University Press: Cambridge, UK, 2004.
3. Xia S, Gan L, Wang K, et al. J. Am. Chem. Soc. 2016; 138: 13493-
13496.
11
12
93
94
4. Anderson K W, Ikawa T, Tundel R E, Buchwald S L. J. Am.
Chem. Soc. 2006; 128: 10694-10695; Willis M C, Angew. Chem.
Int. Ed. 2007; 46: 3402-3404; Chen G, Chan A S C, Kwong F Y.
Tetrahedron Lett. 2007; 48: 473-476; Gallon B J, Kojima R W,
Kaner R B, Diaconescu P L. Angew. Chem. Int. Ed. 2007; 46:
7251-7254; Schulz T, Torborg C, Schaffner B, Huang J, Zapf A,
Kadyrov R, Borner A, Beller M. Angew. Chem. Int. Ed. 2009; 48:
918-921; Sergeev A G, Schulz T, Torborg C, Spannenberg A,
Neumann H, Beller M. Angew. Chem. Int. Ed. 2009; 48: 7595-
7599.
13
14
88
0
a Reagents and conditions: aryl bromide (0.5 mmol), Cu2O (0.05 mmol), L-
Que (0.05 mmol), 25 % ammonia (5 mL), 100 oC, air. b Isolated yield (flash
column chromatography on silica gel).
5. Tlili A, Xia N, Monnier F, Taillefer M, Angew. Chem. Int. Ed.
2009; 48: 8725 –8728; Zhao D, Wu N, Zhang S, Xi P, Su X, Lan
J, You J. Angew. Chem. Int. Ed. 2009; 48: 8729-8732.
6. Jing L, Wei J, Zhou L, Huang Z, Lia Z, Zhou X. Chem. Commun.
2010; 46: 4767-4769; Wang D, Kuang D, Zhang F, Tang S, Jiang
W. Eur. J. Org. Chem. 2014; 2: 315–318.
7. Xu H, Liang Y, Cai Z, Qi H, Yang C, Feng Y. J. Org. Chem.
2011; 76: 2296-2300.
Scheme 1. Attempted reaction of methyl 2-bromobenzoate.
8. James J K. Chem. Review. 1995; 95: 2189-2196; Kurosawa K,
Nagase T, Chida N. Chem. Comm. 2002; 208: 1280-1281.
9. Wu Y, Jiang S, Li G, Zhang G, Zou J, Xu R. W.O. 2014107942,
2014.
10. Xiao Y, Xu Y, Cheon H, Chae J. J. Org. Chem. 2013; 78: 5804-
5809; Wang D, Kuang D, Zhang F, Tang S, Jiang W. Eur. J. Org.
Chem. 2014; 315-318.
When methyl 2-bromobenzoate was used, 2-aminobenzamide
was isolated in 80% yield, indicating that the ester moiety was not
compatible with these reaction conditions.
3. Conclusions
An economical and eco-friendly copper-catalyzed selective
hydroxylation and amination protocol was developed. A variety of
phenols and aryl amines were synthesized from the corresponding
aryl iodides and bromides in moderate to high yields. The process
employing L-Que, a by-product of the rubber industry, was
conducted in water under air and validated on the 100 g scale, thus
constituting a practical and eco-friendly protocol.
11. Thakur K G, Sekar G. Chem. Commun. 2011; 47: 6692–6694.
12. Wacker D A, Varnes J G, Malmstrom S E, Cao X, Hung C, Ung
T, Wu G, Zhang G, Zuvich E, Thomas M A, Keim W J, Cullen M
J, Rohrbach K W, Qu Q, Narayanan R, Rossi K, Janovitz E,
Lehman-McKeeman L, Malley M F, Devenny J, Pelleymounter M
A, Miller K J, Robl J A. J. Med. Chem. 2007; 50: 1365-1379;
Swanger S A, Vance K M, Acker T M, Zimmerman S S, DiRaddo
J O, Myers S J, Bundgaard C, Mosley C A, Summer S L,
Menaldino D S, Jensen H S, Liotta D C, Traynelis S F, ACS
Chem. Neurosci. 2018; 9: 306–319.
Conflicts of interest
There are no conflicts to declare
.
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Acknowledgments

5
Highlights
 New application of L-quebrachitol.
 A green method for hydroxylation and
amination of aryl halides was developed.
 100 gram-scale synthesis.